Process for the production of 4,6-diamino-5-cyano-3-aryl-isoxazolo [5,4-b]p

ABSTRACT

Process for the production of 4,6-diamino-5-cyano-3-aryl-isoxazole [5,4-b] pyridines having the formula: ##STR1## wherein (a) R 1  and R 2  are --H or (b) R 1  is --Cl and R 2  is --H, or (c) R 1  is --CH 3  and R 2  is --H or (d) R 1  is --NO 2  and R 2  is --H, or (e) R 1  is --H and R 2  is --NO 2 . 2-Amino-1-propane-1,1,3-tricarbonitrile having the formula: ##STR2## is reacted with a benzohydroxamino acid chloride having the formula: ##STR3## wherein R 1  and R 2  have the same meaning as above, in the presence of a strong base in at least a molar quantity.

BACKGROUND OF THIS INVENTION

1. Field of this Invention

This invention involves the production of isoxazolo [5,4-b] pyridines.

2. Prior Art

Various processes for the synthesis of isoxazolo [5,4-b] are known. Twoof such processes start out with 5-amino-isoxazoles, which are cyclizedwith β-ketoesters of 1,3-diketones (U.S. Pat. No. 3,381,016) or arereacted with alkoxy methylene malonic or acetic acid esters intoenamines and are subsequently subjected by heating in diphenyl ether orpolyphosphoric acid to cyclization. [(T. Denzel and H. Hoehn, Arch.Pharmaz. 305, 833 (1972), and W. Janssen and T. Denzel, Arch. Pharmaz.308, 471 (1975)].

Benzohydroxyamino acid chlorides were used for the first time asstarting compounds for the production of isoxazoles by Quilico et al.,Rend. ist. lombardo sci. 69, 439 (1936), and Quilico et al., Gazz. chim.ital. 67, 589 (1937), in the case of reaction with β-diketones,β-ketoaldehydes, β-ketoesters, malonic esters, cyano acetic ester andcyano ketones. It is particularly mentioned that the reactions withcyano acetamide and cyano acetic ester lead to 3,4,5-trisubstitutedisoxazoles.

BROAD DESCRIPTION OF THIS INVENTION

An object of this invention is to provide for the production of4,6-diamino-5-cyano-3-aryl-isoxazolo [5,4-b] pyridines in a simplemanner. Other objects and advantages of this invention are set outherein or are obvious herefrom to one ordinarily skilled in the art.

The objects and advantages of this invention are achieved by the processof this invention.

This invention involves a process for production of4-6-diamino-5-cyano-3-aryl-isoxazolo [5,4-b] pyridines having theformula: ##STR4## wherein (a) R¹ and R² are --H, or (b) R¹ is --Cl andR² is --H, or (c) R¹ is --CH₃ and R² is --H, or (d) R¹ is --NO₂ and R²is --H, or (e) R¹ is --H and R² is --NO₂.2-Amino-1-propane-1,1,3-tricarbonitrile having the formula: ##STR5## isreacted with a benzohydroxyamino acid chloride having the formula:##STR6## wherein R¹ and R² have the same meaning as above, in thepresence of a strong base, used in at least a molar quantity (strength).

Preferably the strong base is sodium methylate or aqueous sodiumhydroxide. Preferably the reaction is conducted at a temperature of -10°to +50° C. Preferably the reaction is conducted in water or an alcohol.More preferably the reaction is conducted in methanol or ethanol.Preferably 10 to 25 ml. of the solvent or suspending agent is used pergram of starting material.

By way of summary, this invention involves a process for the productionof 4,6-diamino-5-cyano-3-aryl-isoxazolo [5,4-b] pyridines from2-amino-1-propane-1,1,3-tricarbonitrile and benzobenzohydroxyamino acidin the presence of a strong base.

This invention also includes the intermediates and end products.

DETAILED DESCRIPTION OF THIS INVENTION

Any suitable strong base can be used. Examples of useful alkali metaland alkaline earth metal carbonate basic agents are sodium carbonate,potassium carbonate, magnesium carbonate, cesium carbonate, bariumcarbonate, radium carbonate, calcium carbonate, strontium carbonate,beryllium carbonate, rubidium carbonate and lithium carbonate. Anotheruseful carbonate is ammonium carbonate. Examples of useful alkali metaland alkaline earth hydroxide basic agents are sodium hydroxide,potassium hydroxide, magnesium hydroxide, calcium hydroxide, bariumhydroxide, strontium hydroxide, beryllium hydroxide, cesium hydroxideand lithium hydroxide. Another useful hydroxide is ammonium hydroxide.Examples of useful alkali metal or alkaline earth metal alcoholates oralkoxides basic agents are sodium methoxide, sodium ethoxide andmagnesium methoxide. Examples of useful alkali metal or alkaline earthmetal oxide basic agents are sodium monoxide, potassium monoxide,potassium monoxide, magnesium oxide, barium oxide, strontium oxide,calcium oxide, berylium oxide, cesium oxide, rubidium oxide and lithiumoxide. The preferred strong bases are sodium methylate or ethylatedissolved in methanol, ethanol, and aqueous sodium hydroxide. (Sodiummethylate is sodium methoxide and sodium ethylate is sodium ethoxide.)Mixtures of bases can be used.

The reaction temperature is preferably maintained at ambienttemperatures; a temperature of -10° to +50° C. is suitable for theprocess of this invention.

The reaction can be carried out in water or an alcohol, for examples, aC₁ to C₄ alcohol, such as, methanol, ethanol, propanol, isopropanol andbutanol. Methanol and ethanol are the preferred alcohols. The quantityof solvent or suspension agent is not critical; preferably 10 to 25 mlof solvent or suspending agent per gram of starting material is used.Mixtures of solvents and/or suspending agents can be used.

Whenever 2-amino-1-propene-1,1,3-tricarbonic nitrile (1) and phenylhydroxyamino acid chloride (2a) are reacted in the presence of sodiummethylate as a starting base at a temperature below 15° C., then3-amino-2-cyano-3-(5-amino-3-phenyl-isoxanole-4-yl)-acrylonitrile (3a)can be isolated as the intermediate product. The intermediate product onits part can then be reacted with caustic soda solution at 50° to 100°C. to produce 4,6-diamino-5-cyano-3-phenyl-isoxazolo [5,4-b] pyridine(4a). By diazotizing and boiling down with HNO₂,4-amino-5-cyano-3-phenyl-isoxazole [5,4-b] pyridine can be convertedinto 4-amino-6-hydroxy-3-phenyl-isoxazolo [5,4-b]pyridine-5-carbonitrile (5a).

The reaction of this invention thus follows the following formula(reaction path), wherein:

in the

a formulas is: R¹ =--H, R² =--H

b formulas is: R¹ =--Cl, R² =--H

c formulas is: R¹ =--CH₃, R² =--H

d formulas is: R¹ =--NO₂, R² =--H

e formulas is: R¹ =--H, R² =--NO₂ ##STR7##

The products of this invention, namely the4,6-diamino-5-cyano-3-phenylisoxazolo [5,4-b] pyridines and itscompanion 4b-e compounds, and 4-amino 6-hydroxy-3-phenyl-isoxazolo[5,4-b] pyridine-5-carbonitrile are useful as a tranquilizer, anantiinflammatory agent, an antiasthamatic (Chemical Abstracts 78, 4236Q,4235P and 16162A, Chemical Abstracts 80, 82964F, and Chemical Abstracts85, 21450S) or for plant grow regulation (Chemical Abstracts 84,59279K). Also utility by analogy is involved.

This invention also includes compounds 4b-e which have the formula:##STR8## wherein:

4b is: R¹ =--Cl, R² =H

4c is: R¹ =--CH₃, R² =H

4d is: R¹ =--NO₂, R² =H

4e is: R¹ =--H, R² =NO₂

EXAMPLE 1 4,6-Diamino-5-cyano-3-aryl-isoxazolo [5,4-b] pyridine (4a-e)

4a: 0.7 g (5 mmole) of compound (1) and 1.0 g (6.45 mmole) of compound(2a) are shaken in 10 ml of 2 N NaOH for 2 minutes at ambienttemperature. The reaction mixture is mixed with 10 ml of H₂ O, and theprecipitate is sucked off (removed) and contacted with diluted NaOH. Theyield was 0.4 g (32 percent) of colorless prisms, from glacial aceticacid, having a melting point of 280° C.

For the production of compounds (4b to 4e) one proceeds analogously, butinstead of NaOH, sodium methylate solution can also be used. For theanalytical and spectroscopic data see Tables 1 and 2 below.

EXAMPLE 23-Amino-2-cyano-3-(5-amino-phenyl-isoxazole-4-yl)-acrylonitrile (3a)

A suspension of 1.3 g (10 mmole) of compound (1) in 15 ml of absoluteethanol is added to a freshly prepared sodium methylate solution (0.23 gof Na in 15 ml of EtOH) while stirring. The reaction mixture is cooledto -5° C. To this a solution 0.7 g (11 mmole) of compound (2a) in 8 mlof EtOH is added drop by drop, so that the temperature does not riseabove 15° C. Then after 1 hour, the solution is stirred again. Theprecipitate is sucked off (removed), digested with acetic acid andsucked off (removed once more. The yield was 2.0 g (80 percent) ofyellow bars, from nitrobenzene, having a melting point of 300° C. Dataconcerning the product is:

    ______________________________________                                        C.sub.13 H.sub.9 N.sub.5 O (251.2)                                                   C,          H,      N,                                                        percent     percent percent                                            ______________________________________                                        Calc.:   62.15         3.61    27.87                                          Found:   62.18         3.63    27.93                                          ______________________________________                                    

IR(KBr): 3470, 3360, 3240 (NH₂), 2205 (HN), 1635, 1590 (C═C) cm⁻¹.

EXAMPLE 3 4,6-Diamino-5-cyano-3-phenyl-isoxazolo [5,4-b] pyridine (4a)

0.5 g (2 mmole) of compound (3a) is dissolved in 20 ml of 2 N NaOH, andheated to boiling for 5 minutes. After cooling, the precipitate issucked off (removed). The yield is 0.25 g (50 percent) of colorlessneedles, from glacial acetic acid.

EXAMPLE 4 4-Amino-6-hydroxy-3-phenyl-isoxazolo [5,4-b]pyridine-5-carbonitrile (5a)

0.4 g (1.59 mmole) of 3,6-diamino-5-cyano-3-phenyl-isoxazolo [5,4-b]pyridine (4a) is dissolved in 25 ml of 6 N HCl in heat. Then 5 ml of H₂O is added and mixed drop by drop with a solution of 0.4 g of NaNO₂ in 5ml of H₂ O. The solution is heated to boiling for 60 minutes. Theprecipitate is sucked off (removed) hot. The yield is 0.2 g (50 percent)of colorless plates, from glacial acetic acid, having a melting point of251° C.

For the production of compounds (5b to 5e) one proceeds analogously.

                                      TABLE I                                     __________________________________________________________________________    Isoxazolo-pyridine (4a-e) Product                                             Analytical Data                                                                             Percent                                                                       Yield;                                                          isoxazolo [5,4-b] pyridine                                                                  Melt. Sum-Formula                                                                          Recrystal-  Analysis                               (Compound 4)  Point, °C.                                                                   (Mole Mass                                                                           lized From  C  H  N  Cl                            __________________________________________________________________________    a 4,6-Diamino-5-cyano                                                                       32    C.sub.13 H.sub.9 N.sub.5 O                                                           Glacial Acetic                                                                        Calc.                                                                             62.15                                                                            3.61                                                                             27.87                              3-phenyl    280   (251.2)                                                                              Acid    Found                                                                             62.50                                                                            3.68                                                                             27.07                            b 3-(p-Chlorophenyl)-4,6-                                                                   42    C.sub.13 H.sub.8 N.sub.5 OCl                                                         Nitrobenzene                                                                          Calc.                                                                             54.65                                                                            2.82                                                                             24.52                                                                            12.41                           diamino-5-cyano                                                                           300   (285.7)        Found                                                                             54.72                                                                            2.81                                                                             24.09                                                                            12.11                         c 4,6-Diamino-5-cyano                                                                       69    C.sub.14 H.sub.11 N.sub.5 O                                                          Nitrobenzene                                                                          Calc.                                                                             63.38                                                                            4.18                                                                             26.41                              3-(p-tolyl) 300   (265.3)        Found                                                                             63.51                                                                            4.20                                                                             26.56                            d 4,6-Diamino-5-cyano-                                                                      37    C.sub.13 H.sub.8 N.sub.6 O.sub.3                                                     Nitrobenzene                                                                          Calc.                                                                             52.71                                                                            2.72                                                                             28.37                              3-(p-nitrophenyl)                                                                         300   (296.2)        Found                                                                             51.65                                                                            2.77                                                                             28.16                            e 4,6-diamino-5-cyano-                                                                      75    C.sub.13 H.sub.8 N.sub.6 O.sub.3                                                     Dioxane/H.sub.2 O                                                                     Calc.                                                                             52.71                                                                            2.72                                                                             28.37                              3-(o-nitrophenyl)                                                                         290   (296.2)        Found                                                                             52.95                                                                            2.82                                                                             28.37                            __________________________________________________________________________

    ______________________________________                                        Spectroscopic Data (IR-Spectra                                                And Mass Spectra) For Compounds (4a to 4e)                                    Characteristic,                                                                         IR-Bands, (cm.sup.31 1) In KBr,                                                                     MS-Data;m/e -                                 --NH.sub.2                                                                              --CN      --C═C   Values (Percent)                              ______________________________________                                        a   3450, 3340                                                                              2200      1630, 1600                                                                                 --                                       b   3460, 3360,                                                                             2210      1640, 1590                                                                                 --                                           3220                                                                      c   3450, 3340,                                                                             2200      1635, 1600                                                                              265 (62), 264 (80),                             3210                          249 (10), 237 (12),                                                           221 (11), 209 (10),                                                           194 (40), 148 (37),                                                           120 (35), 91 (100).                         d   3460, 3350,                                                                             2210      1640, 1590                                                                                 --                                           3210                                                                      e   3460, 3340,                                                                             2200      1635, 1595                                                                              296 (53), 266 (3),                              3210                          250 (8), 195 (10),                                                            176 (30),                                                                     148 (100),                                                                    120 (85).                                   ______________________________________                                    

What is claimed is:
 1. Process for the production of a4,6-diamino-5-cyano-3-arylisoxazolo [5,4-b] pyridine having the formula:##STR9## wherein (a) R¹ and R² are --H, or (b) R¹ is --Cl and R² is --H,or (c) R¹ is --CH₃ and R² is --H, or (d) R¹ is --NO₂ and R² is --H, or(e) R¹ is --H and R² is --NO₂, comprising reacting2-amino-1-propane-1,1,3-tricarbonitrile having the formula: ##STR10##with a benzohydroxyamino acid chloride having the formula: ##STR11##wherein R¹ and R² have the same meaning as above, in the presence of astrong base used in a form of at least a molar quantity.
 2. Processclaimed in claim 1 wherein the strong base is sodium methylate inmethanol or aqueous sodium hydroxide.
 3. Process as claimed in claim 1wherein the reaction is conducted at a temperature of -10° to +50° C. 4.Process as claimed in claim 1 wherein the reaction is conducted in wateror an alcohol.
 5. Process as claimed in claim 1 wherein 10 to 25 ml. ofthe solvent or suspending agent is used per gram of starting material(1).
 6. Process as claimed in claim 1 wherein the reaction is conductedin methanol or ethanol.
 7. Process for producing4-amino-6-hydroxy-3-phenylisoxazolo [5,4-b] pyridine-5-carbonitrilehaving the formula: ##STR12## which comprises diazotizing the product ofclaim 1 and then boiling down the diazotized product of claim 1 withHNO₂.
 8. 4,6-diamino-5-cyano-3-phenyl-isoxazolo [5,4-b] pyridine havingthe formula: ##STR13## wherein (a) R¹ and R² are --H, or (b) R¹ is --Cland R² is --H, or (c) R¹ is --CH₃ and R² is --H or (d) R¹ is --NO₂ andR² is --H, or (e) R¹ is --H and R² is --NO₂. 9.4-Amino-6-hydroxy-3-phenyl-isoxazolo [5,4-b] pyridine-5-carbonitrilehaving the formula: ##STR14##